Sequence Note: Reduced Sensitivity to Strain-Specific Neutralization of Laboratory-Adapted Feline Immunodeficiency Virus after One Passage in Vivo: Association with Amino Acid Substitutions in the V4 Region of the Surface Glycoprotein

1996 ◽  
Vol 12 (2) ◽  
pp. 173-175 ◽  
Author(s):  
MANCARLO CAMMAROTA ◽  
DONATELLA MATTEUCCI ◽  
MAURO PISTELLO ◽  
ELISA NICOLETTI ◽  
SIMONE GIANNECCHINI ◽  
...  
Keyword(s):  
Amino Acid ◽  
Feline Immunodeficiency Virus ◽  
Surface Glycoprotein ◽  
Amino Acid Substitutions ◽  
Immunodeficiency Virus

scholarly journals Evolution of Two Amino Acid Positions Governing Broad Neutralization Resistance in a Strain of Feline Immunodeficiency Virus over 7 Years of Persistence in Cats

2003 ◽  
Vol 10 (6) ◽  
pp. 1109-1116 ◽  
Author(s):  
Mauro Pistello ◽  
Donatella Matteucci ◽  
Simone Giannecchini ◽  
Francesca Bonci ◽  
Olimpia Sichi ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Amino Acid ◽  
Feline Immunodeficiency Virus ◽  
Surface Glycoprotein ◽  
Immunodeficiency Virus ◽  
Viral Surface

ABSTRACT Fresh isolates of lentiviruses are characterized by an outstanding resistance to antibody-mediated neutralization. By investigating the changes that occurred in a neutralization-sensitive tissue culture-adapted strain of feline immunodeficiency virus after it was reinoculated into cats, a previous study had identified two amino acid positions of the surface glycoprotein (residues 481 and 557) which govern broad neutralization resistance (BNR) in this virus. By extending the follow-up of six independently evolving in vivo variants of such virus for up to 92 months, we now show that the changes at the two BNR-governing positions not only were remarkably stereotyped but also became fixed in an ordered sequential fashion with the duration of in vivo infection. In one variant, the two positions were also seen to slowly alternate at determining BNR. Evidence that evolution at the BNR-governing positions was accompanied, and possibly driven, by changes in the antigenic makeup of the viral surface brought about by the mutations at such positions is also presented.

scholarly journals Feline Immunodeficiency Virus-Infected Cat Sera Associated with the Development of Broad Neutralization Resistance In Vivo Drive Similar Reversions In Vitro

2001 ◽  
Vol 75 (18) ◽  
pp. 8868-8873 ◽  
Author(s):  
Simone Giannecchini ◽  
Donatella Matteucci ◽  
Aldo Ferrari ◽  
Mauro Pistello ◽  
Mauro Bendinelli
Keyword(s):  
Tissue Culture ◽  
Feline Immunodeficiency Virus ◽  
Surface Glycoprotein ◽  
Virus Variant ◽  
Humoral Immune ◽  
Immunodeficiency Virus ◽  
Escape Mutants ◽  
Intervening Factors

ABSTRACT We previously reported that, upon reinoculation into cats, a neutralization-sensitive, tissue culture-adapted strain of feline immunodeficiency virus constantly reverted to the broad neutralization resistance typical of primary virus isolates and identified residue 481 in the V4 region of the surface glycoprotein as a key determinant of the reversion. Here, we found that well-characterized immune sera, obtained from cats in which such reversion had occurred, selected in tissue culture in favor of virus variants that also had a neutralization-resistant phenotype and had amino acid 481 changed, thus indicating that the host's humoral immune response is capable of driving the reversion in the absence of other intervening factors. In contrast, a second group of immune sera, elicited by a virus variant that had already reverted to neutralization resistance in independent cats, induced the emergence of escape mutants lacking broad neutralization resistance and neutralized fewer virus variants. It is proposed that the viral variants used to produce the two sets of sera may have generated different antibody repertoires.

scholarly journals Mapping of the CXCR4 Binding Site within Variable Region 3 of the Feline Immunodeficiency Virus Surface Glycoprotein

2008 ◽  
Vol 82 (18) ◽  
pp. 9134-9142 ◽  
Author(s):  
Magnus Sundstrom ◽  
Rebecca L. White ◽  
Aymeric de Parseval ◽  
K. Jagannadha Sastry ◽  
Garrett Morris ◽  
...  
Keyword(s):  
Amino Acid ◽  
Feline Immunodeficiency Virus ◽  
Amino Acid Sequences ◽  
Full Length ◽  
Surface Glycoprotein ◽  
Binding Studies ◽  
Virus Surface ◽  
Immunodeficiency Virus ◽  
Feline Model ◽  
V3 Region

ABSTRACT Feline immunodeficiency virus (FIV) shares with T-cell tropic strains of human immunodeficiency virus type 1 (HIV-1) the use of the chemokine receptor CXCR4 for cellular entry. In order to map the interaction of the FIV envelope surface unit (SU) with CXCR4, full-length FIV SU-Fc as well as constructs with deletions of extended loop L2, V3, V4, or V5 were produced in stable CHO cell lines. Binding studies were performed using these proteins on 3201 cells (CXCR4hi CD134−), with or without the CXCR4 inhibitor AMD3100. The findings established that SU binding to CXCR4 specifically requires the V3 region of SU. Synthetic peptides spanning the V3 region as well as a panel of monoclonal antibodies (MAbs) to SU were used to further map the site of CXCR4 interaction. Both the SU V3-specific antibodies and the full-length V3 peptide potently blocked binding of SU to CXCR4 and virus entry. By using a set of nested peptides overlapping a region of SU specifically recognized by CD134-dependent neutralizing V3 MAbs, we showed that the neutralizing epitope and the region required for CXCR4 binding are within the same contiguous nine-amino-acid sequence of V3. Site-directed mutagenesis was used to reveal that serine 393 and tryptophan 394 at the predicted tip of V3 are required to facilitate entry into the target cell via CXCR4. Although the amino acid sequences are not identical between FIV and HIV, the ability of FIV to bind and utilize both feline and human CXCR4 makes the feline model an attractive venue for development of broad-based entry antagonists.

scholarly journals During Readaptation In Vivo, a Tissue Culture-Adapted Strain of Feline Immunodeficiency Virus Reverts to Broad Neutralization Resistance at Different Times in Individual Hosts but through Changes at the Same Position of the Surface Glycoprotein

2001 ◽  
Vol 75 (10) ◽  
pp. 4584-4593 ◽  
Author(s):  
Mauro Bendinelli ◽  
Mauro Pistello ◽  
Daniela Del Mauro ◽  
Giancarlo Cammarota ◽  
Fabrizio Maggi ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Amino Acid ◽  
Feline Immunodeficiency Virus ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Surface Glycoprotein ◽  
Intermediate Phenotype ◽  
Immunodeficiency Virus

ABSTRACT The broad resistance to antibody-mediated neutralization of lentiviruses recently isolated from infected hosts is a poorly understood feature which might contribute to the ability of these viruses to persist and to the failure of experimental vaccines to protect against virulent viruses. We studied the underlying molecular mechanisms by examining the evolution of a neutralization-sensitive, tissue culture-adapted strain of feline immunodeficiency virus upon reinoculation into specific-pathogen-free cats. Reversion to broad neutralization resistance was observed in seven of seven inoculated animals and, in individual hosts, started to develop between less than 4 and more than 15 months from infection. After comparison of the envelope sequences of the inoculum virus, of an additional 4 neutralization-sensitive in vitro variants, and of 14 ex vivo-derived variants (6 neutralization sensitive, 5 resistant, and 3 with intermediate phenotype), a Lys→Asn or →Glu change at position 481 in the V4 region of the surface glycoprotein appeared as a key player in the reversion. This conclusion was confirmed by mutagenesis of molecularly cloned virus. Analysis of viral quasispecies and biological clones showed that the intermediate phenotype was due to transient coexistence of neutralization-sensitive and -resistant variants. Since the amino acid position involved was the same in four of four recent revertants, it is suggested that the number of residues that control reversion to broad neutralization resistance in FIV might be very limited. Amino acid 481 was found to be changed only in one of three putative long-term revertants. These variants shared a Ser→Asn change at position 557 in region V5, which probably collaborated with other mutations in long-term maintenance of neutralization resistance, as suggested by the study of mutagenized virus.

scholarly journals Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1

2013 ◽  
Vol 57 (9) ◽  
pp. 4290-4299 ◽  
Author(s):  
Vici Varghese ◽  
Yumi Mitsuya ◽  
W. Jeffrey Fessel ◽  
Tommy F. Liu ◽  
George L. Melikian ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protease Inhibitor ◽  
Cross Resistance ◽  
Amino Acid Substitutions ◽  
Phenotypic Properties ◽  
The Public ◽  
Immunodeficiency Virus ◽  
The Many ◽  
High Level ◽  
Infectious Molecular Clones

ABSTRACTThe many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI-resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI-resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel's viruses in the context of a correlation network of PI resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activities of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most if not all clinically relevant PI-resistant viruses.

scholarly journals In Vivo Antiretroviral Activity of Stampidine in Chronically Feline Immunodeficiency Virus-Infected Cats

2003 ◽  
Vol 47 (4) ◽  
pp. 1233-1240 ◽  
Author(s):  
Fatih M. Uckun ◽  
Chun-Lin Chen ◽  
Peter Samuel ◽  
Sharon Pendergrass ◽  
T. K. Venkatachalam ◽  
...  
Keyword(s):  
Dose Level ◽  
Peripheral Blood Mononuclear Cells ◽  
Feline Immunodeficiency Virus ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Antiretroviral Activity

ABSTRACT Here we report the antiretroviral activity of the experimental nucleoside reverse transcriptase inhibitor (NRTI) compound stampidine in cats chronically infected with feline immunodeficiency virus (FIV). Notably, a single oral bolus dose of 50 or 100 mg of stampidine per kg resulted in a transient ≥1-log decrease in the FIV load of circulating peripheral blood mononuclear cells in five of six FIV-infected cats and no side effects. A 4-week stampidine treatment course with twice-daily administration of hard gelatin capsules containing 25 to 100 mg of stampidine per kg was also very well tolerated by cats at cumulative dose levels as high as 8.4 g/kg and exhibited a dose-dependent antiretroviral effect. One of three cats treated at the 25-mg/kg dose level, three of three cats treated at the 50-mg/kg dose level, and three of three cats treated at the 100-mg/kg dose level (but none of three control cats treated with placebo pills) showed a therapeutic response, as evidenced by a ≥1-log reduction in the FIV load in peripheral blood mononuclear cells within 2 weeks. The previously documented in vitro and in vivo antiretroviral activity of stampidine against primary clinical human immunodeficiency virus type 1 isolates with genotypic and/or phenotypic NRTI resistance, together with its favorable animal toxicity profile, pharmacokinetics, and in vivo antiretroviral activity in FIV-infected cats, warrants further development of this promising new NRTI compound.

scholarly journals A Budding Yeast Model for Human Disease Mutations in the EXOSC2 Cap Subunit of the RNA Exosome

2020 ◽  
Author(s):  
Maria C. Sterrett ◽  
Liz Enyenihi ◽  
Sara W. Leung ◽  
Laurie Hess ◽  
Sarah E. Strassler ◽  
...  
Keyword(s):  
Amino Acid ◽  
Budding Yeast ◽  
Amino Acid Substitutions ◽  
Missense Mutations ◽  
Subunit Gene ◽  
Rna Targets ◽  
Genes Encoding ◽  
Rna Exosome ◽  
Transcriptomic Changes

AbstractRNA exosomopathies, a growing family of tissue-specific diseases, are linked to missense mutations in genes encoding the structural subunits of the conserved 10-subunit exoribonuclease complex, the RNA exosome. Such mutations in the cap subunit gene EXOSC2 cause the novel syndrome SHRF (Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies). In contrast, exosomopathy mutations in the cap subunit gene EXOSC3 cause pontocerebellar hypoplasia type 1b (PCH1b). Though having strikingly different disease pathologies, EXOSC2 and EXOSC3 exosomopathy mutations result in amino acid substitutions in similar, conserved domains of the cap subunits, suggesting that these exosomopathy mutations have distinct consequences for RNA exosome function. We generated the first in vivo model of the SHRF pathogenic amino acid substitutions using budding yeast by introducing the EXOSC2 mutations in the orthologous S. cerevisiae gene RRP4. The resulting rrp4 mutant cells have defects in cell growth and RNA exosome function. We detect significant transcriptomic changes in both coding and non-coding RNAs in the rrp4 variant, rrp4-G226D, which models EXOSC2 p.Gly198Asp. Comparing this rrp4-G226D mutant to the previously studied S. cerevisiae model of EXOSC3 PCH1b mutation, rrp40-W195R, reveals that these mutants have disparate effects on certain RNA targets, providing the first evidence for different mechanistic consequences of these exosomopathy mutations. Congruently, we detect specific negative genetic interactions between RNA exosome cofactor mutants and rrp4-G226D but not rrp40-W195R. These data provide insight into how SHRF mutations could alter the function of the RNA exosome and allow the first direct comparison of exosomopathy mutations that cause distinct pathologies.

Sign in / Sign up

Export Citation Format

Share Document